The present invention relates to the use of the monocyte growth factor CD137 for promoting the proliferation of peripheral monocytes and in particular the use of CD137 for the treatment of various disease states which are treatable in a novel manner by means of the proliferation-promoting action of CD137.
Peripheral monocytes of the blood and the macrophages originating from them from body cavities and tissues are a constituent of the mononuclear phagocytic system of the body. In particular, monocytes and macrophages are effector cells of the non-specific immune defence system of the body. Monocytes develop over a number of intermediate stages from the haematopoietic stem cells in the bone marrow. They circulate over a period of time of approximately 20 to 30 hours in the blood. From there, they migrate into the various organs and tissue systems and there develop to site-specific macrophages. Here, the surrounding tissue has a formative influence on them and they develop additional functions. A differentiation is therefore made according to tissue type, for example macrophages of the lung (alveolar macrophages), of the abdominal cavity (peritoneal macrophages), of the spleen (splenic macrophages), of the liver (Kupffer cells), of the joints, of the bone (osteoclasts), of the connective tissue, of the brain and of the kidney.
Monocytes and macrophages have a central position in the context of the inflammatory reactions occurring in the body. In non-inflamed tissue, the object of macrophages is the elimination of old cells. Moreover, they produce a large number of soluble factors which are important for communication within the immune system. If the cells are involved, however, in an inflammatory process, they are in an activated state with greatly modified phenotypical and functional properties. In this case, they exert important effector functions influencing the course of the disease. These include phagocytosis and intracellular destruction of microorganisms, immune complexes and damaged cells, but also the antibody-dependent and -independent cytotoxicity reactions against tumour cells, parasites and virus-infected cells. Moreover, monocytes and macrophages are of central importance in the induction and regulation of the immune response. Namely, they are moreover secretory highly active cells, which affect the immune response by means of the increased release of cytokines.
CD137 is a member of the tumour necrosis factor receptor families and is moreover known (Kwon, B. S., et al., Proc Natl Acad Sci USA 86:1963, 1989; Schwarz H. et al., Gene 134:295,1993; Alderson, M. R., et al., Eur J Immunol 24:2219,1994) under the names ILA or 4-1BB (homologues from the mouse). CD137 is expressed by activated lymphocytes and monocytes, the expression by primary cells being dependent on activation (Schwarz H. et al., Blood 85:1043, 1995). The CD137 expression is rapidly inducible, for example, by activation of T lymphocytes with phytohaemagglutin in (PHA) or phorbol-12-myristate-13-acetate (PMA). In monocytes, CD137 is inducible by activation with lipopolysaccharide (LPS), IL-1xcex2 and PMA. In B lymphocytes, CD137 expression is induced by antibodies against cell-surface immunoglobulin or TMA, and by transformation with EBV (Epstein-Barr virus). In non-lymphoid cells (such as, in particular, chondrocytes), CD137 is strongly inducible by the proinflammatory cytokine IL-1xcex2. Soluble forms of CD137 are produced by differential splicing and can be detected in raised concentrations in sera of patients with rheumatoid arthritis (Michel, J., et al., Eur J Immunol 28:290, 1998). The gene for human CD137 is on chromosome 1p36 in a cluster of related genes (Schwarz, H., et al., Biochem Biophys Res Com 235:699, 1997).
It is moreover known of recombinant CD137 protein that in immobilized form it brings about an activation of monocytes. The results of the activation is an increased expression of pro-inflammatory cytokines, an inhibition of the anti-inflammatory cytokine IL-10 and the induction of activation markers, such as ICAM (Langstein J. et al., J. Immunol 160-2488, 1998). A life-prolonging or proliferation-promoting action on monocytes is not described therein.
As already mentioned above, monocytes have a key function in the context of the immune response, and are of essential importance for the production of benign immune reactions against tumours and pathogens. Attracted by signals, such as, for example, from cytokines, they migrate from the blood circulation to the site of the inflammation. An accumulation of monocytes and macrophages is a characteristic feature of chronic inflammations. This accumulation is further promoted by cytokines, which are released at the site of inflammation, such as, for example, macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3), which have a favorable effect on the survival of monocytes and macrophages (Young, D. A., J Immunol 145:607, 1990; Xing, Z., et al., Am J Respir Cell Mol Biol 6:212, 1992; Bratton, D. L., et al., J Clin Invest 95:211, 1995).
Until now, it was assumed of peripheral monocytes and macrophages that they are not capable of proliferation, i.e. of replication (cf. Xing, Z. et al., Supra; van Furth, R., et al., Blood 54-485, 1979).
From the above details, it is evident that the treatment of numerous disorders, such as, for example, tumours, infections by bacteria, fungi or viruses, could be markedly improved if an increased phagocytosis and intracellular destruction of microorganisms, immune complexes and damaged cells, and also an improved anti-body-dependent or -independent cytotoxicity reaction against tumour cells, microorganisms and cells infected thereby could be produced by replication of the monocytes/macrophages.
It is moreover known that various therapeutic forms of treatment, such as, for example, the chemotherapy or radiation therapy of cancer patients, and the administration of immunosuppressants, drastically reduces the number of monocytes and macrophages. After completion of therapeutic procedures of this type, it is as a rule desirable to increase the number of monocytes/macrophages again to values in the normal range and consequently to stabilize the immune system of the patient again.
It is therefore the object of the present invention to make available a route which makes it possible to specifically increase the number of peripheral monocytes and consequently the number of macrophages, in order to make possible an improved treatment of disease states which are associated with an inadequate number of active monocytes/macrophages.
It was surprisingly possible to achieve this object starting from the finding that the cell-surface protein CD137, which is known per se, and functional analogues thereof, contrary to previous assumptions, induces the proliferation of peripheral monocytes independently of the haematopoietic stem cells. This surprisingly opens up a large number of new therapeutic application possibilities for CD137.